The traditional cancer therapy is based on organ- and tissue-centric treatment modalities, which do not tackle the root problems and which frequently lead to therapy resistance and disease relapse. The advent of the genomic era has led to an explosive revelation of genetic information on cancers and has highlighted some common genomic variations across cancer types. A new dogma is thus emerging that combinations of a few key genomic abnormalities in critical biological pathways may underlie broad arrays of malignant development and/or aggression. Targeting these common and vital points of tumorigenesis may result in much greater impact on cancer therapy across the spectrum than selecting narrowly focused, individual cancer specific targets. Our recent clinical and laboratory investigations have for the first time identified EDD, a novel nuclear protein and HECT-domain E3 ubiquitin ligase of potentially fundamental importance, as an essential master player in many vital physiological pathways as well as a cross-cancer regulator of tumorigenesis and anti-tumor immunity. We find that EDD?s potent tumorigenic activities are exerted paracrine primarily through inhibiting dendritic cell (DC) differentiation and T cell activation via certain yet to be defined secreted soluble immunosuppressors, whereas its metastasis-promoting property is purely ?cell-intrinsic?, independent of the immune system and even of its E3 ubiquitin ligase activity. Bioinformatic analyses reveal that EDD gene alterations (predominantly amplifications) occur in 25% of prostate cancer, 23% of breast and ovarian cancers, close to 20% of bladder, liver, uterine, and stomach cancers, and in 10% of many other types of solid tumors. In addition, genetic lesions in EDD are strongly associated with reduced survival rates in breast and ovarian cancer patients. Yet, EDD?s biological functions and mechanisms remain highly obscure. In this proposal of limited scope, we will focus the investigations on (1) delineating the molecular mechanisms whereby EDD controls DC differentiation and immune responses in paracrine through its regulation of tumor-secreted immunosuppressors; (2) identifying EDD?s interacting proteins including its E3 ligase substrates and non-substrate partners. These limited objectives, once accomplished, will likely generate the critical knowledge and essential experimental datasets required for an R01 application, which will lay out the blueprint that is going to ultimately lead to new paradigms and dramatic changes in cancer therapeutic landscape in a groundbreaking manner because targeting EDD or its major signaling mediators will bring strong clinical benefits to patients of a wide array of highly aggressive and therapy-resistant malignancies by undermining the very foundation of tumorigenesis and cancer metastasis of a pivotal cross-cancer regulator.